Zearalenone reduction

ABSTRACT

A METHOD FOR REDUCING ZEARALINONE TO ZERALANOL IN WHICH THE PRODUCT CONTAINS A MAJOR AMOUNT OF THE HIGHMELTING DIASTEREOISOMER AND A MINOR AMOUNT OF THE LOWMELTING DIASTEREOISOMER OF ZEARALANOL IS DISCLOSED. ZEARALENONE IS CATALYTICALLY REDUCED WITH HYDROGEN FOR A TIME SUFFICIENT TO REDUCE THE ZEARALENONE TO ZEARALANOL IN THE PRESENCE OF A PLATINUM CATALYST AND A WEAK ACID HAVING A FIRST ACID IONIZATION CONSTANT OF FROM ABOUT 1X10**4 TO 5X10**1 IN WATER AT ABOUT 25:C. AND SAID ACID NOT BEING ITSELF REDUCED UNDER THE CONDITIONS OF THE ZEARALENONE REDUCTION.

United States Patent 3,808,233 ZEARALENONE REDUCTION Edward B. Hodge,Terre Haute, Ind., assignor to Commercial Solvents Corporation, TerreHaute, Ind. No Drawing. Filed Sept. 26, 1972, Ser. No. 292,449 Int. Cl.C07d 9/00 U.S. Cl. 260-343.2 F 12 Claims ABSTRACT OF THE DISCLOSURE Amethod for reducing zearalenone to zearalanol in which the productcontains a major amount of the highmelting diastereoisomer and a minoramount of the lowmelting diastereoisomer of zearalanol is disclosed.Zearalenone is catalytically reduced with hydrogen for a time suflicientto reduce the zearalenone to zearalanol in the presence of a platinumcatalyst and a weak acid having a first acid ionization constant of fromabout 1X10 to X in water at about 25 C. and said acid not being itselfreduced under the conditions of the zearalenone reduction.

This invention relates to a method for reducing zearalenone to a mixtureof the highand low-melting point diastereoisomers of zearalanol.

The terms zearalenone and zearalanol conform with the nomenclature in anarticle in Tetrahedron Letters, Pergamon Press, Ltd., No. 27, pp.3109-3114 (1966). When zearalenone, having the formula is converted tozearalanol, having the formula r n)a (CHM by reduction of the olefinicbond and the ketone group in the presence of hydrogen, a mixture ofdiastereoisomers of zearalanol is formed. This reduction, carried out inthe presence of a Raney nickel catalyst, is disclosed in U.S. Pat. No.3,239,345. The diastereoisomers differ in melting point. The disclosedreduction provides an approximately 55:45 ratio of the high-meltingpoint to the lowmelting point diastereoisomer.

Disclosed in U.S. Patent application Ser. No. 25,265, filed Apr. 2,1970, now U.S. Pat. 3,697,548, and in corresponding Belgium Pat. No.765,130, is a method of catalytically reducing zearalenone to a mixturecontaining a major amount of the diastereoisomer of zearalanol havingthe higher melting point and a minor amount of diastereoisomer ofzearalanol having the lower melting point in the presence of a strongacid, that is, an acid which is essentially completely ionized in anaqueous solution. This process, while producing a good conversion ofzearalenone to the diasteroisomer of zearalanol having the highermelting point with a relatively rapid rate of conversion, requiresreaction vessels which are extremely resistant to strong acids orrequires frequent replacement of reaction vessels due to corrosion.

It was also disclosed in United States patent application Ser. No.25,265, now U.S. Pat. No. 3,697,548, and corresponding Belgium Pat. No.765,130, that a weak acid, e.g., acetic acid, was found unsatisfactoryfor promoting the reduction of zearalenone to the high boiling diastero-3,808,233 Patented Apr. 30, 1974 isomer of zearalanol. For example,acetic acid only provides about a 15 to 20 percent reduction ofzearalenone to zearalanol after a six hour reaction period.

The product can be separated utilizing a procedure disclosed in ExamplesI and II of U.S. Pat. No. 3,574,235 in the name of Vernon V. Young. Bothdiasteroisomers of zearalanol are useful as anabolic substances for oraland parenteral administration to animals in the manner disclosed in U.S.Pat. No. 3,239,345.

It has now been found that certain weak acids may be employed in aprocess for the catalytic reduction of zearalenone to a mixturecontaining a major amount, e.g., greater than weight percent, forexample, about weight percent or more, of the diastereoisomer ofzearalanol having the higher melting point and a minor amount, e.g.,less than 45 weight percent, for example, about 40 weight percent orless, of the diasteroisomer of zearalanol having the lower meltingpoint.

In accordance with the present invention, the reduction of zearalenoneis conducted in the presence of a solvent, a platinum catalyst, andcertain weak acids for a time sufiicient to reduce the zearalenone tozearalanol and provide a high ratio of the high melting pointdiastereoisomer to the low melting point diastereoisomer. The productwill generally contain a major amount of the high melting pointdiastereoisomer of zearalanol. The weak acid employed in the process ofthe present invention has a first acid ionization constant of from about1X10- preferably 5X10- to 5 X 10- in an aqueous solution at 25 C., andwill not itself be reduced to a weaker acid under the conditionsemployed for the zearalenone reduction.

The term weak acid, as used herein, refers to acids which are less thanessentially completely ionized in water (except in extremely dilutesolution). It conforms with standard nomenclature as found in, forexample, Fundamental Concepts of Chemistry, Appleton-Century-Crofts(1969), pp. 233 and 234. Such weak acids include weak acids as well asmoderately strong acids. Exemplary of the weak acids which may beemployed in the present invention are citric acid, tartaric acid,phosphoric acid, and oxalic acid.

The zearalenone can be prepared and purified as described in Examples IIand III of U.S. Pat. No. 3,239,345. The zearalenone is advantageouslysuspended or dissolved in a suitable solvent, preferably a loweralkanol, e.g., ethanol, normal propyl alcohol, isopropyl alcohol and theI like, preferably those containing from 1 to 3 carbon atoms andparticularly ethanol. zearalanol-producing amounts of a weak acid, oftena small amount, e.g., about 0.001 to 5 volume percent (based on thesolvent), preferably from about 0.01 to 3 volume percent or equivalentweight, of weak acid is added to the solvent. The reaction may beconducted in the presence of, for instance, about 2 to 10 volume percentof water.

The zearalenone and solvent can advantageously be present in amounts of,for example, from about 1 to 25 grams of zearalenone per cc. of thesolvent. A platinum catalyst supported on a suitable carrier, e.g.,charcoal, is advantageously used. Generally, the catalyst contains fromabout 0.01 to about 10 weight percent of platinum and is employed incatalytic amounts, generally a catalyst to zearalenone weight ratio offrom about 0.00l:1 to 1:1.

The zearalenone is reduced in the presence of hydrogen under reducingconditions for a time suflicient to reduce substantially all of thezearalenone. Advantageously, the reduction can be carried out at atemperature of from about 15 to 100 C., preferably about 20 to 60 C.with a hydrogen pressure generally of from about 20 to 1000 p.s.i.,preferably 25 to 100 p.s.i., for at least 3, preferably about 3 to 8,hours. After the reduction, the platinum catalyst is removed from thereaction mixture, e.g., by filtration, andthe resulting'mixture can; asa-matter of convenience, be concentrated, to say, a volume of from about0.5 to 0.1 of the reaction mixture volume, and filtered again. Thefiltered, concentrated solution can be diisomer of zearalanol comprisingcatalytically reducing luted with-water, for example, in an amount offrom zearalenone with hydrogen under reducing conditions in about 2 to 4volumes of the concentrated solution, by addthe presence ofzearalanol-producing amounts of a weak ing water slowly while stirringthe solution. The resulting acid and catalytic amounts of platinumcatalyst, said weak solution is advantageously allowed to stand at roomtemacid having a first acid ionization constant of from about peraturefor a time suflicient to allow the zearalanol to 1 10 to 5 10- inaqueous solution and said weak precipitate from the solution which canbe about 2 to 4 acid not itself being reduced to a weaker acid under thehours or more. Filtration of the mixture yields the white reducingconditions.

crystals of zearalanol containing a major amount of the 2. The method ofclaim 1 wherein the reducing conhigh melting diastereoisomer and a minoramount of the ditions include temperatures from about to 100 C. lowmelting diastereoisomer which can be separated as 15 and a hydrogenpressure from about to 1000 p.s.i. and noted above. the catalyst isemployed in a catalyst to zearalenone weight The following examples arepresented to further illusratio from about 0.001:1 to 1:1. trate theinvention and are not in limitation thereof. 3. The method of claim 2wherein the reduction is con- EXAMPLE I ducted in the presence of asolvent consisting essentially 20 of a lower alkanol solvent.

Three grams (g) of zearalenone and 3 milliliters of 4. The method ofclaim 3 wherein the lower alkanol 85% phosphoric acid are added to 200ml. of ethanol at contains from 1 to 3 carbon atoms and the solventconroom temperature, after flushlflg With nitrogen, tains from about0.001 to 5 volume percent (based on g. of a 5 percent platinum oncharcoal catalyst is added. the l f h weak i The solutlon charged mm anAdams reducmg P 5. The method of claim 2 wherein the catalytic reacratusand g g hydrogen for 6 hours i room tion is carried out with reducingconditions including temperature un era y rogen pressure of p.s.1. Theresultperatures from about 20 to and a hydrogen Pres mg reduced mlxture1S filtered, concentrated to ml. Sure from about 25 to Si nd filteredagain. Then 400 ml of water are added to a 6. The method of claim 3wherein the solvent conthe mixture slowly w1th stirring. After 3 hoursat room 30 ak f b 1 temperature the mixture is filtered to give 2 61 gof tams we an m an amount mm a out to 3 V0- ume percent, based on thevolume of the solvent. zearalanol which is analyzed to be about 76% ofthe hlgh 7 The method of claim 2 wherein the reduction is com meltingdiastereoisomer and 24% of the low melting diastereoisomer ducted 1n thepresence of water in an amount of about 2 5 to 10 volume percent.

EXAMPLES H t 1X 8. The method of claim 1 wherein the weak acid has Thefollowing examples were conducted in essentially a first acid ionizationconstant of from about 5 1O to the same procedure as that set forth inExample 1 except 5X 10-1- ditferent solvents and weak acids areemployed. The re- 9. The method of claim 2 wherein the weak acid issults of these examples are set forth in Table I. 40 tartaric acid.

TABLE I Amount zearalanol recovered Ratio of high Amt Time iit ir ei 5733251251? Example Solvent Weak acid hrs. charged e perceni'.

II; Ethanol Tartaric 2 7 III- d d 2 8 IV. Isopropanol ..do 2 7 Vt-Bntanol Phosphoric-- 2 7 VI Ethanol Oxalic 2 7 VII nn cum- 2 7 VIIL;do Succinic"--- 2 7 IX do Maleic 2 7 1 Product obtained in mostlyzearalanone the results obtained are comparable to that of Example 65VIH.

10. The method of claim 2 wherein the weak acid is phosphoric acid.

11. The method of claim 2 wherein the weak acid is oxalic acid..

12. The method of claim 2 wherein the weak acid is citric acid.

References Cited UNITED STATES PATENTS 3,687,982 8/1972 Young 260343.23,697,548 10/1972 Hodge 260343.2

JOHN M. FORD, Primary Examiner

